The inability of current treatment modalities to impact on the natural history of lung and esophageal cancers, together with the prevalence of these malignancies, underscores the need for more fundamental appreciation of molecular mechanisms of aerodigestive tract carcinogenesis. In previous studies we have utilized recombinant viral vectors to demonstrate the impact of restoration of cyclin D1, p16, and p53 expression in lung and esophageal cancer cells. These mutations, which disrupt G1 Restriction Point control are known to occur early during multistep aerodigestive tract carcinogenesis, hence they are appropriate targets for intervention in established malignancies as well as their precursor lesions.In conjunction with Dr. Dao Nguyen, Senior Investigator, Thoracic Oncology Section, recent efforts have focused on the evaluation of pharmacologic agents which might achieve molecular end points without the complexities and limitations of gene therapy strategies dependent upon viral vectors. We have observed that the synthetic flavone, flavopiridol, mediates profound cell cycle arrest and apoptosis in esophageal cancer cells irrespective of histology or tumor suppressor gene status, and that pretreatment of esophageal cancer cells with flavopiridol markedly enhances their sensitivity to paclitaxel. These data have provided the rationale for a recently-approved protocol evaluating flavopiridol alone versus flavopiridol with paclitaxel in esophageal cancer patients. Documentation of efficacy in established cancers may support the evaluation of flavopiridol for the chemoprevention of aerodigestive tract cancers in high risk individuals.Approximately 30% of lung and esophageal cancers overexpress the erbB-2/p185 oncogene which is believed to mediate resistance to chemotherapeutic agents such as cisplatin or paclitaxel. Downregulation of erbB-2/pl85 gene function can be achieved by antisense techniques, tyrosine kinase inhibitors, or monoclonal antibodies that bind to the extracellular domain of the pl85 protein. Recently, we have observed rapid, dose-dependent depletion of pl85 protein in lung and esophageal cancer cells treated with the ansamycin analogue 17-allylamino geldanamycin (17-AA GA). Reduction of p185 expression by 17-AA GA markedly enhanced the cytotoxicity of taxol in these cells; specifically, a 3 to over 40-fold increase in paclitaxel sensitivity was observed in cells treated with 17-AA GA/paclitaxel as compared to cells exposed to paclitaxel alone. This enhancement effect was achieved at nanomolar concentrations of 17-AA GA. Flow cytometry analysis revealed that combination drug treatment induced pronounced G2/M arrest and subsequent apoptosis within 72 hours of drug exposure. These preclinical data support the evaluation of 17-AA GA and paclitaxel in patients with thoracic neoplasms.In additional studies we have attempted to utilize demethylating agents and histone deacetylase inhibitors to induce expression of tumor suppressor genes such as p16 and ARF which are frequently inactivated by promoter hypermethylation in thoracic neoplasms. Interestingly, these experiments have converged with parallel studies in our laboratory demonstrating induction of NY-ESO-1 and MAGE-3 cancer-testis antigen expression in lung cancer cells by 5 Aza-2 deoxycytidine (decitabine). Our studies have shown that cancer testis antigen expression is more readily induced in lung cancer cells relative to normal human bronchial epithelial cells, fibroblasts, or EBV transformed lymphocytes--perhaps due to genome-wide demethylation which is known to occur during malignant transformation. A phase I trial designed to evaluate decitabine-mediated induction of tumor antigen and tumor suppressor gene expression in lung cancer patients is currently open for patient accrual. A Phase II study designed to evaluate Depsipeptide mediated gene induction and apoptosis in lung cancer patients will be open in the near future.Nearly 20% of all cancer patients succumb to isolated pulmonary metastases, and additional efforts in our section have been directed toward the evaluation of regional drug delivery to the lungs. A sheep model of isolated lung perfusion has been established , and pharmacokinetic studies using paclitaxel have been completed. Additional pharmacologic agents and gene constructs delivered via nonviral techniques will be evaluated using this model. These animal experiments have provided the the rationale for analysis of isolated lung perfusion utilizing paclitaxel and moderate hyperthermia in patients with unresectable pulmonary malignancies.The following clinical protocols submitted by the Thoracic Oncology Section have been reviewed by the NCI-IRB and are expected to be open for patient accrual in the near future:1)Randomized Phase II Study of Continuous Three Day Flavopiridol Infusion Alone vs. Flavopiridol In Combination With Three Hour Taxol Infusion inEsophageal Cancer Patients.2)Phase I Study of Decitabine Mediated Induction of Tumor Antigen and Tumor Supressor Gene Expression in Lung Cancer Patients. 3) Phase II Study of Gene Induction Mediated by Four-Hour Intravenous Depsipeptide (FR901228/NSC630176) Infusion in Lung Cancer Patients.4)Phase I Study of Isolated Lung Perfusion with Paclitaxel and Moderate Hyperthermia in Patients with Unresectable Pulmonary Malignancies.
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